Substituted naphtho pyrazoles

ABSTRACT

Substituted naphtho (1,2-c) pyrazoles, e.g., 3-(4-pyridyl)-2Hnaphtho(1,2-c)-pyrazole, are useful as non-estrogenic antifertility agents.

tte ttes Ulntlnnm et at.

SUBSTIITUTED NAPHTHO PYRAZOLES Inventors: Robert V. Coombs Chatham; William J. Houlihan, both of Mountain Lakes, NJ.

Assignee: Sandoz-Wander, Inc, Hanover, NJ.

Filed: Feb. 20, 1973 Appl. No.: 333,557

Field] of Search 260/296T, 310 R, 294.8 R,

[ Oct. 22, 1974 [56] References Cited 7 UNITED STATES PATENTS 3,624,102 ll/l97l Brown et al 260/310 R Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm-Gerald D. Sharkin; Robert S. Honor; Thomas O. McGovern [57] ABSTRACT Substituted naphtho [1,2-c] pyrazoles, e.g., 3-(4- pyridyl)-2H-naphtho[l,2-c]-pyrazole:, are useful as non-estrogenic anti-fertility agents.

3 jla ilns, No lirawinggs SUBSTITUTED NAPHTHU PYRAZOLES It should be noted that the compounds of structures (la) and (lb) are considered equivalent in the art and This n ent on relates to ap lpy ol are known to exist in both tautomeric forms. derivatives. More particularly it relates to 3-aryl and The compounds of formulas (I) can be prepared by 3-heterocyclic derivatives of naphtho [1,2-c] pyrazole 5 the following reaction scheme: and their use in pharmaceutical compositions.

R in V v 7 W R H Ar 2 Ar catalyst R 2 N r1 N i N H (II) (I) The compounds of this invention may be represented where by the following formula: R R Ar and the proviso are as set out above.

R mm 7' i W a The compounds of formula (I) are prepared by dehydrogenating a compound of formula (II) in the pres- (I) ence of a noble metal dehydrogenation catalyst. The particular noble metal catalyst used is not critical, but platinum or palladium, either alone or supported on carbon, alumina, talc, and the like is preferred, and 5 percent palladium on carbon is especially preferred.

where H W Although a solvent is not required, it is preferred that Ar is R the reaction be carried out in the presence of an inert I t 3 3O solvent such as the lower alkanols having 1 to 4 carbon U U I or atoms, aliphatic or aromatic hydrocarbons, haloge- U q nated hydrocarbons, straight chain ethers or cyclic H ethers. The particular solvent used is not critical, but and a the lower alkanols, such as methanol, ethanol and butano] and/or dioxane are preferred. The temperature of the reaction also is not critical, but it is generally carried out between 50 and 200C preferably at the reflux temperature of the system. lt is also preferred that the reaction be run for from 48 hours to 5 days. The prod- 40 uct is recovered in the usual manner, e.g., by evaporation and crystallization.

The compounds of formulas (I) may also be prepared by the following reaction scheme:

R,, R R and R each independently represent hydrogen, halo having an atomic weight of about 19 to 36, lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl and the like; lower alkoxy, i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, isopropoxyand the like, or trifluoromethyl or R and R or R and R together independently represent methylenedioxy attached to adjacent carbon atoms, provided that when R, and R or R and R are independently trifluoromethyl or tertiary butyl, they are on other than adjacent carbon atoms, and

lCl A1" NH2NH2 0 H H0 (IV) r 11 r bl acid addition salts Where ai s g y accep a 8 R R Ar and the proviso are as set out above. The pyrazole ring (A) in the compounds of formula h Compounds of formula (I) are prepfired by (I) Can have the following Structures fluxmg a compound of the formula (III) with a hydrazine of formula (IV) in diethylene glycol. It is preferred Ar that the reaction be run for from about 1 to 8 hours and 3 that it be carried out under an inert atmosphere e.g. nitro en ar on, helium and the like. The roduct is iso- L 2 g g p lated by standardtechmques, e.g., recrystallization.

H The compounds of formula (I) may also be prepared (Ib) in accordance with the following reaction scheme:

Ring

Closure R NI'IIII'ICO-AI where is preferred that the reaction be carried out in the presh 2 Ar and the Proviso are as defined Previously 5 ence of an inert solvent such as the lower alkanols having 1 to 4 carbon atoms, aliphatic or aromatic hydro- The C mpo n of formula are P p y g carbons, halogenated hydrocarbons, straight chain closure of a compoun of formula with P P ethers or cyclic ethers. The particular solvent used is mus (l/chloride of phosphorus Pentachloride in an not critical, but the lower alkanols, such as methanol, inert solvent. Although the particular solvent used in ethanol or butanol or dioxahe are f d Th the reaction IS r101 Critical, the pfeffil'ed Solvents are perature of the reaction also is not critical, but it is genafommic hydrocarbons Such as benzene toluenfh erally carried out between and 200C, preferably at lene and the like or excess phosphorus oxychloride or the fl temperature f the System For optimum pentachloride- The tempmature at which the reaction suits it is preferred that the reaction be run for from 8 is carried out is not critical, but it is preferred that the 25 hours to 5 days h product i recovered i h usual reaction be run at about to 200C especially at the manner elg. by evaporation and crystallization,

reflux temperature of the system. The time also is not The compounds of formula (V) can be prepared accritical, but it is preferred that the reaction be run for cording to the following reaction scheme:

I R CO-Ar (VIII) R R2 2 NIIDIH NHNriCO-An (VII) (V) from 10 to 24 hours. The product is recovered by c o nwhere ventional techniques, for example, recrystallization. R is halo having an atomic weight of about 35 to 80 The compounds of formula (II) are prepared accordor lower lk as d fi d above d ing to the following procedure: R R Ar and the proviso are as set out above.

0 Ar NH NH R J R i (IV) iii II I) (II) where The compounds of formula (V) are prepared by t, 2, Ar and theprovlso are as defined above. treating a compound of formula (VII) with a com- The compounds of formula (II) are prepared by pound of formula (VIII). Although a solvent is not nectreating a compound of formula (VI) with hydrazine of essary, it is preferred that the reaction be carried out formula (IV). The reaction is preferably carried out in an inert solvent such as lower alkanols having 1 to under acidic catalysis which can be provided by a min- 4 carbon atoms aliphatic or aromatic hydrocarbons, eral acid such as hydrochloric acid, sulfuric acid, and halogenated hydrocarbons, straight chain or cyclic the like, an organic acid such as p-toluenesulfonic or ethers or excess compound of formula (VIII). The paracetic acid or a Lewis acid such as boron trifluoride. ticular solvent used is not critical, but the preferred sol- The preferred acids are p-toluenesulfonic acid and vents are the lower alkanols such as methanol, ethanol,

boron trifluoride. Although a solvent is not required, it butanol and the like. The temperature of the reaction 6 is not critical, but it is normally carried out between 35 solvent, temperature or time used inthe reaction are and 150C, preferably at the reflux temperature of the not critical. system. It is also preferred that the reaction be runfor The tosylate and mestylate can be prepared from the from 5 to 48 hours. The product is recovered by conchlorine or bromine substituted compound by treatventional techniques, e.g., evaporation. 5 ment with a tosylate or mesylate salt, such as sodium or The compounds of formula (VI) are prepared in acpotassium tosylate or mesylate in an inert solvent such cordance with the following reaction scheme: as lower alcohols, toluene or benzene. The reaction is ArCHO Base I Ar R Y X R O (IX) (to) where preferably carried out at temperatures between to Y is a leaving group and 70 especially between to 40 for a period of 2 to R R Ar nd th provi o are s set t ab v 10 hours, preferably 4 to 7 hours. The particular sol- The compounds of formula (VI) are prepared by vent used, the temperature and the time of the reaction treating the compounds of formula (IX) with the comare not critical. pounds of formula (X) under basic conditions in an The hydrazine 0f fefmula and m ny Oflhe 00 inert solvent. It is preferred that the reaction be run in 25 Pounds and are an inert atmosphere such as argon, helium and espeknown and are prepared by procedures disclosed in the cially nitrogen. The leaving group Y in formula (IX) literature The c mp n 0f fbfmllla can be any of the conventional leaving groups emand not sp ically d closed in the ployed in such a reaction such as chlorine, bromine, ioliterature may e prepared by analogous methods using dine, tosylate, mesylate and the like. The preferred known tarting materials. leaving group is the halogens, especially chlorine or The COmPOUHdS 0f formula are Useful ec e bromine. The basic conditions for the reaction are pro they possess pharmacological activity in animals. In vided by alkali or alkali earth metal hydroxides, alkali par i lar. he compounds are useful as anti-fertility metal lower alkoxides, tertiary aliphatic and aromatic agents as indicated by their activity in female Wistar amines and tertiary cyclic amines such as pyridine and rats which are injected daily with 2 mg. of the comthe like. Although the particular solvent used is not pound for eight successive days starting on the day of critical, the lower alkanols having 1 to 4 carbon atoms vaginal cornification. At the time of the 4th injection, such as methanol, ethanol, butanol and the like are esmales of known fertility are cohabitated with the fepecially preferred, in particular the lower alkanol cormales (one female with one male) until the end of the responding to the alkali metal alkoxide when used. The treatment period. The males are separated from the fetemperature of the reaction is not critical, but is is genmales 24 hours following the lastinjection. The females erally carried out between 0 and 30C, preferably are sacrificed six days later, and examined for the presabout 5 to l0C. Although the time is not critical, it is ence or absence of implantation sites. preferred that the reaction be run for from 1 to 5 hours. The use of the compounds as anti-fertility agents is The product is recovered by standard techniques e.g., further indicated by their luteolytic properties which by crystallization or distillation. results in the compounds being abortifacient agents. The compounds of formula (IX) are prepared by well The luteolytic activity is determined using pseudopregknown procedures from compounds of the formula: nant rabbits treated with corn oil or compound of formula (I) (1-100 mg per day) suspended in corn oil on days 3 through 8 of pseudopregnancy. Blood samples are obtained daily throughout the length of pseudopregnancy. Plasma samples are analyzed for progestin in) content according to the method of Johansson et al. (Endocrinology 82, 143, I968). The compound is R judged active if plasma progestin levels are similar to 2 O pretreatment values on day 12 of pseudopregnancy. where Abortifacient activity is also determined in female R R and the proviso are as set out above. proestrous rats (Royal Hart, Wistar strain) selected The compounds of formula (IX) may be obtained by from a colony and caged with fertile males. On the folstandard procedures from compounds of formula (XI). lowing day, pregnancy is confirmed by the presence of For example, the chlorine or bromine substituted comspermatozoa in the vaginal smear. On the seventh day pounds can be prepared by treating the compound of following mating, the females are treated with 'l to 30 formula (XI) with chlorine or bromine, preferably in an milligrams of the compound to be tested. The animals inert solvent such as acetic acid, chloroform or carbon are injected daily for a total of seven days; and on the tetrachloride. The reaction can be carried out at temeighth day following the first injection, the animals are peratures from room temperature to 50 over a period killed and the uterus checked for the presence of abof l to 12 hours, preferably 3 to 6 hours. The particular sence of implantation sites.

The compounds of formula (I), when used as antifertility agents, exhibit none of the estrogenic effects and side effects exhibited by the steroidal type compounds used for these purposes.

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers or adjuvants, and may be administered orally in such forms as tablets, capsules, elixirs, suspensions and the like, e.g., bucally or sub-lingually as a tablet, parenterally in the form of an injectable solution or suspension or in special forms such as suppositories, e.g., vaginal inserts, pessaries,

and the like. Depending upon the compound employed and the mode of administration the exact dosage utilized may vary.

Furthermore, the compounds of formula (I) may be similarly administered in the form of their non-toxic pharmacautically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly, are included within the scope of the invention. Representative of the acid addition salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, 'benzenesulfonate, and the like. i

In general, satisfactory results are obtained when the compounds-of formula (I) are administered as antifertility agents at a daily dosage of about 1.0 milligrams to about 200 milligrams orally, subcutaneously or intramuscularly per kilogram of animal body weight. This daily dosage is preferably administered 1 to 4 times a day or in sustained release form. For most large mammals, such as primates, the total daily dosage is from about 1 milligram to about 600 milligrams. Dosage forms suitable for internal use comprise from about 0.25 milligrams to about 300 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

A representative formulation suitable for intramuscular administration once a day in fertility control is an injectable suspension prepared by standard techniques which contain the following:

EXAMPLE 1 3-(4-pyridyl.)-2H-naphtho[ l ,Z-clpyrazole Step A: 3-( 4-pyridyl)-spiro[ 1 ,2,3,4 tetrahydronaphthalene-2,2'-oxirane]-l-one To a stirred solution of l 1.3 g of 2-bromo-a-tetralone and 5.5 g. of pyridine-4-carboxaldehyde in 20 ml. of methanol under nitrogen is added at 5 to C a solution of sodium methoxide in methanol (prepared by is used in place of the 2-bromo-oz-tetralone above there is obtained a. 3-(4-pyridyl)-spiro[6-chloro-1,2,3,4-

tetrahydronaphthalene-2,2 '-oxirane]- 1 -one; b. 3 -(4-pyridyl)-spiro[6-methyl- 1 ,2,3,4-

tetrahydronaphthalene-Z,2 '-oxirane 1 -one; c. 3 -(4-pyridyl)-spiro[ 6,7-dimethoxy- 1 ,2,3,4-

tetrahydronaphthalene-2 ,2-oxirane]- 1 -one; d. 3 4-pyridyl)-spiro[ 6-trifluoromethyl-l 2,3,4-

tetrahydronaphthalene-2,2'-oxirane]-l-one or e. 3 '-(4-pyridyl )-spiro[6,7-methylenedioxy- 1 ,2,3,4- tetrahydronaphthalene-Z,2 '-oxirane]- 1 -one respectively. When an equivalent amount of f. 2-thiophenealdehyde; g. 2-furfural; h. p-tolualdehydc i. m-trifluoromethylbenzaldehyde j. 3,4-methylenedioxybenzaldehyde k. p-chlorobenzaldehyde 0r 1. p-methoxybenzaldehyde is used in place of the pyridine-4-carboxyaldehyde above, there is obtained f. 3-(2-thienyl)-spiro[ 1,2,3,4-tetrahydronaphthalene-2,2-oxirane]-l-one; g. 3'-(2-furyl)-spiro[ l ,2,3,4-tetrahydronaphthalene- 2,2'-0xirane]-l-one; h. 3-(p-toxyl)-spiro[ l,2,3,4-tetrahydronaphthalene- 2,2-oxiranel-l-one; i. 3 '-(m-trifluoromethylphenyl)-spiro[ 1 ,2,3,4-

tetrahydronaphthalene-2,2-oxirane]- 1 -one; j. 3 '-(3,4-methyledioxyphenyl)-spiro[ 1 ,2,3,4-

tetrahydronaphthalene-Z,2-oxirane]- 1 -one; k. 3 -(p-chlorophenyl)-spiro[ l,2,3,4-

tetrahydronaphthalene-Z,2-oxirane]- 1 -one or 1. 3'-(p-methoxyphenyl)-spiro[ 1 ,2,3,4- tetrahydronaphthalene-2,2'-oxirane 1 -one respectively. Step B: 4,5-dihydro-3-(4-pyridyl)-2H-naphtho[1,2- c]pyrazole Three grams of 3'-(4-pyridyl)-spiro[ l,2,3,4- tetrahydronaphthalene-Z,2-oxirane]-l-one in 10 ml. of ethyl alcohol is added to 18 ml of 98 percent hydra-- zine, 3.5 ml of acetic acid and 12 ml of dioxane and re fluxed for 12 hours. On cooling the mixture, 4,5- dihydro-3-(4-pyridyl)-2H-naphtho[ l ,2-c]pyrazole precipitates and is recovered by filtration (m.p. of base 229C; m.p. of hydrochloride salt 300C).

Following the above procedure but using an equivalent amount of a. 3 4-pyridyl )-spiro[6-chloro- 1 ,2,3,4-

tetrahydr0naphthalene-2,2-oxirane]-l-one; b. 3 4-pyridyl )-spiro[6-methyl- 1 ,2,3,4-

tetrahydronaphthalene-Z,2 '-oxirane]- l-one; c. 3 -(4pyridyl )-spiro[ 6,7-dimethoxy- 1 ,2,3,4-

tetrahydronaphthalene-2,2'-oxirane]- l-one;

j. 2-(1-hydroxynaphthyl)-3,4-methylenedioxyphenyl ketone; k. 2-(lhydroxynaphthyl)-4-chlorophenyl ketone or 1. 2-( l-hydroxynaphthyl)-4-methoxyphenyl ketone in place of the 2-(l-hydroxynaphthyl)-4-pyridyl ketone, there is obtained a. 7-chloro-3-(4 pyridyl)-2H-naphtho[1,2-

c]pyrazole;

7-methyl-3-(4-pyridyl)-2H-naphtho[ 1 ,2- c]pyrazole;

7,8-dimethoxy-3-(4-pyridyl)-2H-naphtho[ 1,2- c]pyrazole;

7-trifluoromethyl-3(4-pyridyl)-2H-naphtho[ l ,2- c]pyrazole;

. 7,8-methylenedioxy-3-(4-pyridyl)-2H- f. 3-(2-thienyl)-2H-naphtho[ l ,2-c]pyrazole;

g. 3-(2-furyl-2H-naphtho[ l ,2-c]pyrazole;

i. 3-(m-trifluoromethylphenyl)-2H-naphtho[ l ,2- c]pyrazole;

j. 3-(3,4 methylenedioxyphenyl)-2H-naphtho[ 1,2-

c]pyrazole;

3-(p-chlorophenyl)-2H-naphtho[ l,2-c]pyrazole,

1. 3-(p-methoxyphenyl)-2H-naphtho[ 1,2-c]pyrazole respectively.

EXAMPLE 3 A solution of 16 grams (0.10 mole) of l-naphthyl hydrazine, 15.1 grams (0.10 moles) of ethyl isonicotinate and 300 ml. of'isopropanol are stirred and refluxed for 48 hours. The solvent is removed in vacuo and the re-' sultant 2-( lnaphthyl)-isonicotinic acid hydrazide is added to 125 ml. .of phosphorous oxychloride and stirred and refluxed for about hours. The reaction mixture is then concentrated in vacuo and the resultant simi-solid dissolved in about 250 ml. methylene dichloride. The methylene dichloride layer is washed with 100 ml of cold 2N potassium hydroxide, 100 ml. of water, dried with magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethanol/ether yields 3-(4-pyridy)-2H-naphtho[l,2-c]pyrazole, mp. 27 l-273.

When the above process is carried out using a equivalent amount of a. 6-chloro-l-naphthyl hydrazine b. 6-methyll -naphthyl hydrazine c. 6,7-dimethoxy-l-naphthyl hydrazine d. 6-trifluoromethyl-l-naphthyl hydrazine or e. 6,7-methylenedioxy-l-naphthyl hydrazine in place of the l-naphthyl hydrazine there is obtained a. 7-chloro-3-(4-pyridyl)-2H-naphtho[ l ,2-

c]pyrazole;

7-methyl-3-(4-pyridyl)-2H-naphtho[1,2- c]pyrazole;

c. 7,8-dimethoxy-3-(4-pyridyl)-2H-naphtho[1,2-

c]pyrazole; d. 7-trifluoromethyl-3-(pyridyl)-2H-naphtho[1,2-

c]pyrazole, or 7,8-methylenedioxy-3-(4-pyridyl)-2H- naphtho[ 1 ,2-c]-yrazole, respectively.

Following the above procedure, but using an equivalent amount of f. 2-thienyl carboxylic acid, ethyl ester;

g. 2-furyl carboxylic acid, ethyl ester;

h. p-toluic acid, ethyl ester;

i. m-trifluoromethylbenzoic acid, ethyl ester;

j. 3,4-methylenedioxybenzoic acid, ethyl ester;

k. p-chlorobenzoic acid, ethyl ester or 1. p-methoxybenzoic acid, ethyl ester in place of the ethyl isonicotinate there is obtained f. 3-(2-thienyl)-2H-naphtho[ 1,2-c]pyrazole;

g. 3-(2-furyl)-2H-naphtho[ l ,2-c]pyrazole;

h. 3-(p-tolyl)-2H-naphtho[1,2-c]pyrazole;

i. 3-(m-trifluoromethylphenyl)-2H-naphtho[ 1,2-

j. 3-(3,4-methylenedioxyphenyl)-2H-naphtho[1,2-

c]pyrazole; k.

1. B-(p-methoxyphenyl)-2H-naphtho[ 1,2-c]pyrazole respectively. What is claimed is: l. A compound of the formula where ring A represents the structures Ar Ar J L N--H I-I-N- Ar is and 3. The compound of claim 1 which is 3-(4-pyridyl)- a 3-(p-chlorophenyl)-2H-naphtho[ l,2-c]pyrazole, 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 in which Ar is pyridyl.
 3. The compound of claim 1 which is 3-(4-pyridyl)-2H-naphtho(1, 2-c)pyrazole. 